1Note: Indications may not apply to all members of the group equally.
There may be dose forms for some indications and species, but not others. Note also that
details of larvae vs adults are not noted in every case.
Refs: Barragry'95
Webster, LT, Jr., GG8th'90
USPDI'94
Courtney & Roberson'95

Chemical Groups and General Mechanisms of Antinematodal Drugs

Group/Drug

Mechanism

Effect on Parasite

Macrolide Endectocides

CURRENT1:

Open chloride channels in invertebrates

Binding site GLUTAMATE-gated channels

Site is near GABA-gated sites which may also be potentiated

50% of effect reversed with picrotoxin, a GABA antagonist active at the chloride channel

IVERMECTIN

Adverse effects

Ivermectins are relatively safe for species that have an
approved dose form; horse, dog, cattle, and swine. They have no
known teratogenic effect.

At high doses the ivermectins can cause CNS signs, including lethargy,
ataxia, mydriasis, tremors, and death.

Adverse effects, in horses, of an injectable form that is no longer
avilable may represent signs that could be seen with overdose
(Louisiana study). These signs include eyelid edema, fever, increased
rate and depth of respiration, disorientation, signs of colic,
extreme depression, and death within minutes. Death occurred in
1 horse of 3,316 treated.

DOGS, ESPECIALLY COLLIES(Boraski, 1984) were claimed to have special
sensitivity to ivermectin. Some collie strains developed severe
adverse reactions when given ivermectin at a dose of 100 mg/kg;
16 x the label dose now recommended. At a dose of 6 mg/kg (the
approved dose), the drug is well tolerated in collies and other
breeds of dogs (Lynn'95, p266). A single PO dose of 2 mg/kg and
PO doses of 0.5 mg/kg q1d for 14 weeks were well tolerated by
dogs. Doses greater than 20 mg/kg given to laboratory dogs causes
mydriasis, depression, tremors, ataxia, coma, and death. No teratogenic
effects where observed after giving pregnant bitches repeated
PO doses of 0.5 mg/kg.

There is now a special tablet formulation, HEARTGARD 30
(Merck) for use in preventing heartworms so there is no longer
any reason to use dose forms prepared for other species. Nonetheless,
because it underscores a major principle of therapy, the following
anecdote is worth reading.

<<< AN IVERMECTIN STORY >>>
The following is
an excerpt from a letter written by a practitioner. (Schulze 1984)
"...Recently at the suggestion of a sales representative,
I gave an injection of Eqvalan to a heavily parasitized
canine pup of a large mixed breed (not Collie). Approximately
0.15 cc was given deep intramuscularly (gastrocnemius). The animal
appeared in otherwise good health at presentation. Within one
hour, an agitated client returned with a critically ill animal.
It exhibited just about every imaginable sign, from prostration,
ptyalism, opisthotonos, nystagmus, thrashing and paddling, extensor
rigidity, to coma and death within another 15 minutes. It was
like watching every page of a veterinary toxicology text flashing
before my eyes. Forget the LD-50s!

"This embarrassed veterinarian has given his first and last
ivermectin injection to a canine. Needless to say, I am hesitant
to continue my 0.2% ivermectin oral regimen of successful heartworm
control in the same species." [end of quote]

<<< MORALS >>>
Certain morals can be drawn from
this anecdote. First, be extremely cautious when using new drugs
in species other than those for which they were specifically approved.
Second, route of administration and dose formulation do make a
difference and are often species specific.
<<< MORALS >>>

Many studies have shown that although ivermectin is not approved
for use in cats, single PO doses of 0.024 mg/kg are effective
against Ancylostoma braziliense and Ancylostoma tubaeforme.
A dose of 0.3 mg/kg is required for Toxocara cati. Doses
of 0.024 mg/kg were shown to be effective in preventing Dirofilaria
immitis adults from appearing in infected cats when given
30 to 45 days after artificial infection. Thus, this drug and
dose should be satisfactory as a heartworm preventive when given
q1mo (Lynn'95).

Milbemycin oxime (InterceptorR)

Adverse effects

Tolerated at up to 20-times recommended dose -- 200 mg/kg in dogs

Safe for nursing and pregnant animals

Benzimidazoles

Adverse effects

Teratogenic effects have been shown for albendazole, cambendazole,
oxfendazole, and parbendazole. If these drugs are to be used in
early pregnancy, it must be for good reason and at the lowest
recommended doses.

Acute toxicity is extremely difficult to produce with these
drugs and LD50s are almost impossible to define for drugs such
as thiabendazole and fenbendazole. They are regarded as safe up
to 20 to 30 times the recommended dose. The earliest sign of toxicity
noted in horses with mebendazole is a slight diarrhea.

Pyrimidine derivatives

Pyrantel and Morantel

Adverse effects

No adverse effects were described by Theodorides, 1985. However,
at increasing doses, one would expect signs of neuromuscular blockade
or other evidence of nicotinic action. For example, in humans,
oral doses may cause transient, mild gastrointestinal signs.

Contraindications

of morantel include dairy cows, for which it is not approved [Need
to check '95] . Pyrantel should not be mixed with rations containing
bentonite. (Bentonite is a soft, porous clay from volcanic ash.)

Precautions/comments

Should not use pyrantel, morantel and levamisole together. Pyrantel
is mutually antagonistic with piperazine on membrane potential,
but can be used with organophosphates and certain other antiparasitic
and antimicrobial drugs. Pyrantel can be used in the presence
of Dirofilaria immitis. It can also be used in pregnancy,
nursing, weanlings, and males used for breeding.

Organophosphates

Adverse effects

The adverse effects are discussed with special reference to dichlorvos.
Those of other organophosphates will be very similar.

The margin of safety is very narrow. The drugs are safe to approximately
2-times the recommended dose.

Signs of toxicity are typical of acetylcholinesterase inhibitors
and include evidence of excessive acetylcholine at muscarinic
and nicotinic receptors. Early signs include salivation, lacrimation,
urination, dyspnea, and defecation which have the mnemonic of
SLUDD. Treatment is with atropine and pralidoxime.

Formulations of the organophosphate compounds are very
specific for the target species, especially in flea collars
and in the resins intended for oral administration. For more information
on why a resin formulation intended for one species might be toxic
or ineffective when given to another species consult Roberson
(JBM5th 830-831).

A summary of the Roberson material follows. Dichlorvos is formulated
in resins to make a slow release dose form. Variations
in geometry, size and method of formulation (including coating
or not coating), of pellet plus the quantity of dichlorvos allow
for a range of diffusion rates suitable for different host animals.
Task, for the dog, has smaller pellets and faster release
rate to accomodate the shorter gastrointestinal tract. For swine,
Atgard V has larger pellets and a moderate release rate
for the longer tract. Pellets may contain 20% dichlorvos. A moderate
release rate may cause 50-55% loss during passage through the
tract of swine in 24 hours. Usually, enough dichlorvos is eliminated
in the feces to be effective as an insecticide for fly larvae.

Two principle difficulties associated with dichlorvos are overcome
by resins. First, they decrease the toxicity of the volatile,
toxic drug. Second, they protect the drug within the vehicular
reservoir from moisture to slow hydrolytic degradation.

Contraindications

There are important Contraindications to the use of dichlorvos.
The drug should not be used within a few days of use or exposure
to cholinesterase inhibitors.

An important source of exposure is routine use of these agents
around the owner's premises.

Dichlorvos should not be used concurrently with other anthelmintics,
tranquilizers, muscle relaxants, or modified live-virus vaccines.
The drugs, which may also have actions on the CNS, skeletal muscle,
and/or muscarinic receptors may increase the toxicity of dichlorvos.
Presumably, the live-virus vaccines act as stressors that may
exacerbate the toxicity.

Dichlorvos should not be used in animals with diarrhea or severe
constipation or intestinal blockage.

Puppies and kittens weighing less than 1 lb and less than 10 days
old are not good risks.

Dogs with heartworms should not be treated.

Levamisole (Imidazothiazole derivative)

Adverse effects

Safe up to 5-times recommended dose

signs of CNS and parasympathetic ganglionic stimulation

At 2 to 3- times the recommended dose, cattle lick their lips,
salivate, and shake their head.

At higher doses, one may see excitement, tremors, and death.

dogs: VOMITING, but can control with atropine pretreatment.

dogs: RESTLESSNESS and NERVOUSNESS. -- Should stop Rx for larvae

Piperazines

Lynn95* p247 on Selectivity -- Ascarids are very sensitive to piperazines,
hookworms are refractory

Piperazine

Diethylcarbamazine citrate

Diethylcarbamazine citrate [CaracideR, HetrazanR, etc.]

Adverse effects

RELATIVELY NON-TOXIC.

GASTROINTESTINAL IRRITATION and VOMITION in few animals

Multiple generation studies -- no evidence of problems.

SEVERE REACTIONS in dogs that have circulating microfilariae

shock-like syndrome. release of serotonin and other vasoactive
substances from microfilariae??

Cyproheptadine can antagonize these effects. Cyproheptadine
is an antiserotonin drug with some antihistaminic properties.
It has also recently been reported as being able to cause development
of diabetes mellitus. (Can't remember reference for cyproheptadine/diabetes
link)